Based on the ligand selectivity in the receptor binding assay as seen in different tissues, the sigma receptor was found to consist of two subtypes, the sigma-1 and sigma-2 receptors. The incorrect early assumption that the sigma receptors would be members of the family of opioid receptors has been declined since the early 1990’s. After many years of research, now it has been revealed that the sigma-1 receptor is a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. Evidence was found that the most prominent action of sigma-1 receptors in biological systems is the regulation and modulation of voltage-regulated and ligand-gated ion channels, including Ca(2+)-, K(+)-, Na(+), Cl(-), and SK channels, and NMDA and IP3 receptors. Stimulation of the receptor by sigma-1 agonists causes inhibition of all above-mentioned voltage-gated ion channels, while on the other hand it potentiates ligand-gated channels. In contrast, little is known to date of the sigma-2 receptor which is still to be cloned. Activation of the receptor seems to cause apoptosis.